Method for contemporaneous application of laser energy and localized pharmacologic therapy

ABSTRACT

A method for contemporaneously applying laser energy and locally delivering pharmacologic therapy to a selected site in a body lumen using a liquid core laser angioscope catheter. The method comprises preparing a solution of a pharmacologic agent, inserting the catheter into the lumen, directing the catheter to the site, transmitting visible light to the site, flowing the light transmissive liquid through the catheter, viewing the site, transmitting laser energy through the liquid filled catheter to treat the site, and introducing a flow of the pharmacologic agent in solution into the catheter for contemporaneous discharge at the distal end into the lumen adjacent the site.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method and apparatus forcontemporaneous application of laser energy and localized delivery ofpharmacologic therapy to a site within a body lumen. More specificapplications of the present invention relate to a method and apparatusfor localized treating of vascular thrombosis disorders,atherosclerosis, and tumors.

2. Description of Prior Art

Atherosclerosis, which is a major cause of cardiovascular disease,resulting in heart attacks, is characterized by the progressiveaccumulation of atherosclerotic deposits (known as plaque) on the innerwalls of the arteries. As a result, blood flow is restricted and thereis an increased likelihood of clot formation that can partially orcompletely block or occlude an artery, causing a heart attack. Arteriesnarrowed by atherosclerosis that cannot be treated effectively by drugtherapy are typically treated by medical procedures designed to increaseblood flow, including highly invasive procedures such as coronary arterybypass surgery and less invasive procedures such as balloon angioplasty,atherectomy and laser angioplasty.

Bypass surgery involves opening the patient's chest and transferring avein cut from the patient's leg to the heart to construct a detouraround the occluded artery. Bypass surgery requires prolongedhospitalization and an extensive recuperation period. Furthermore,bypass surgery also exposes the patient to a risk of major surgicalcomplications. Balloon angioplasty is a less invasive and less costlyalternative to bypass surgery and is performed in a hospital cardiaccatheterization laboratory by an interventional cardiologist. In thisprocedure, a balloon-tipped catheter is inserted into a blood vesselthrough a small incision in the patient's arm or leg. The physician usesa guide catheter to feed the balloon through the patient's blood vesselsto the occluded artery. At that point, a guidewire is inserted acrossthe deposits of atherosclerotic plaque, known as lesions, to provide apathway for the balloon catheter. The deflated balloon is advanced overthe guidewire, positioned within the occluded area and inflated anddeflated several times. This inflation and deflation usually tears theplaque and expands the artery beyond its point of elastic recoil. Thus,although no plaque is removed, the opening through which blood flows isenlarged.

Atherectomy employs a rotating mechanical device mounted on a catheterto cut and remove plaque from a diseased artery. Although atherectomy,unlike balloon angioplasty, removes plaque from coronary arteries,existing atherectomy devices are not effective in treating certain typesof lesions.

Laser angioplasty removes plaques by using light, in varying wavelengthsranging from ultraviolet to infrared, that is delivered to the lesion bya fiber optic catheter. Early attempts to develop a laser angioplastysystem used continuous wave thermal lasers that generated heat tovaporize plaque. These laser systems caused charring and significantthermal damage to healthy tissue surrounding the lesion. As a result,thermal laser systems have generally been regarded as inappropriate foruse in the coronary arteries. In contrast, excimer lasers useultraviolet light to break the molecular bonds of atheroscleroticplaque, a process known as photoablation. Excimer lasers use electric,ally excited xenon and chloride gases to generate an ultraviolet laserpulse with a wavelength of 308 nanometers. This wavelength ofultraviolet light is absorbed by the proteins and lipids that compriseplaque, resulting in precise ablation of plaque and the restoration ofblood flow without significant thermal damage to surrounding tissue. Theablated plaque is converted into carbon dioxide and other gases andminute particulate matter that can be easily eliminated.

In laser angioplasty, conventional light guides using fiber optics areused to direct laser energy onto arterial plaque formations to ablatethe plaque or thrombus and remove the occlusion. Individual opticallyconducting fibers are typically made of fused silica or quartz, and aregenerally fairly inflexible unless they are very thin. A thin fiberflexible enough to pass through a lumen halving curves of small radius,such as through arterial lumens from the femoral or the brachial arteryto a coronary artery, typically projects a beam of laser energy of verysmall effective diameter, capable of producing only a very small openingin the occlusion. Moreover, the energy is attenuated over relativelysmall distances as it passes within a thin fiber. Small diameter fiberscan mechanically perforate vessels when directed against the vessel wallas they are passed within the vessel toward the site.

In order to bring a sufficient quantity of energy from the laser to thethrombus or plaque, light guides proposed for use in laser angioplastyusually include a number of very thin fibers, each typically about 50 to200 microns in diameter, bundled together or bound in a tubular matrixabout a central lumen, forming a catheter. Laser energy emerging from asmall number of fibers bundled together produces lumens of suboptimaldiameter which can require subsequent enlargement by, for example,balloon dilation. Such devices do not always remove an adequate quantityof matter from the lesion, and their uses are generally limited toproviding access for subsequent conventional balloon angioplasty.

Although individual fibers of such small dimensions are flexible enoughto negotiate curves of fairly small radius, a bundle of even a few suchfibers is less flexible and more costly. Coupling mechanisms fordirecting laser energy from the source into the individual fibers in alight guide made up of multiple small fibers can be complex. Improperlaunch of the laser energy into such a light guide can destroy thefibers. The directing of laser energy into arteries or veins thus farhas been limited to two-dimensional imaging with fluoroscopy.Frequently, it is not possible to distinguish whether the laser catheteris contacting plaque, normal tissue, or thrombus--all of which have verydifferent therapeutic consequences as well as possible adverse sideeffects.

An alternative to conventional optical fiber technology using fusedsilica fibers or fiber bundles, is the use of fluid core light guides totransmit light into the body, as discussed by Gregory et al. in thearticle "Liquid Core Light Guide for Laser Angioplasty", IEEE Journal ofQuantum Electronics, Vol. 26, No. 12, December 1990, incorporatedherein. While fluid-core light guides may offer improvements of fusedsilica fibers or bundles, initial animal and clinical studies indicateinadequate or only partial removal of thrombus or athleroscleroticmaterial, and a recurrence of athlerosclerosis after treatment.

Another approach to treating atherosclerosis orthrombosis is to degradethrombi and plaque by treatment with various pharmacologic agents. Manytechniques currently exist for delivering medicant and other activeagents to body tissue. These include: oral administration, directinjection into body tissue, and intravenous administration whichinvolves introducing the active agent directly into the blood stream.These delivery mechanisms are systemic, in that they deliver the activeagent via the bloodstream throughout the entire body. Effectivepharmacologic or drug therapy requires achieving adequate concentrationsof an active drug at the site of desired treatment without producingconcentrations of the drug elsewhere in the body that create unwanted ordangerous side effects.

Workers in the field have discovered that many effective drugs which arecapable of treating or curing disease cannot be effectively deliveredsystemically because the concentrations necessary for effectivetreatment produce adverse side effects in other parts of the body. Forexample, in the case of arterial and venous thrombosis, workers in thefield have identified many potent agents which are capable of degradingthrombi, but clinical application of these agents has been limited bybleeding complications which can result in substantially increasedmorbidity and mortality. Moreover, even clinically approved agents suchas streptokinase, urokinase, recombinant tissue plasminogen activatorsor even heparin have limited efficacy in treating acute myocardialinfarction and other thrombotic disorders because they can producesystemic bleeding complications.

One approach to reducing systemic side effects is to introduce acatheter percutaneously, through the skin, near the thrombotic siteunder fluoroscopic guidance. The active agent is then infused in highconcentrations and flowed by the thrombus. There are, however, practicallimits to the duration of such treatment. Prolonged infusion willeventually produce a total accumulated systemic dose of the agentsufficient to create adverse side effects. Enzymatic degradation is inlarge part dependent upon the surface area of the thrombus which isexposed to the enzyme--which is limited to current infusion of enzymeswhich flow by the thrombus. In addition to the great cost of such aninfusion, the prolonged indwelling of the catheter increases morbidity.The ability to administer an active agent locally to the thrombotic sitewithout systemically affecting other tissues or creating complications,would greatly enhance the ability to effectively treat arterial andvenous thrombus.

Another application for delivering an active agent to an internal bodytissue is in treating cancerous tumors. The objective of such treatmentis to concentrate as much of the cancer drug or gene product in thetumor as possible. Typically, workers in the field administer cancerdrugs systemically through the blood stream and then use various meansto localize the drug in the cancerous tumor. Nevertheless, amounts ofthe drug still circulate through the blood stream in sufficientconcentrations to produce adverse side effects and therefore limit thedosages of the drug which can be safely administered.

Accordingly, a need remains for a method and apparatus for locallydelivering an active agent in conjunction with delivering laser energyto internal body tissue. There is a further need for such an apparatusand method for treating atherosclerosis, thrombosis, cancerous tumors,and other internal body tissue.

SUMMARY OF THE INVENTION

The invention provides a method for contemporaneously applying laserenergy and locally delivering pharmacologic therapy to a selected sitein a body lumen using a liquid core laser catheter. The catheterincludes a flexible tube having a distal end for insertion into thelumen, a conduit housed within the tube, means for coupling a flow oflight transmissive liquid from an external source into the conduit,means for transmitting laser energy from an energy source into theconduit, the conduit having a sidewall capable of internally reflectinglight into the liquid in the conduit so that the liquid waveguides thelaser energy through the conduit to the site. The method comprises thesteps of preparing a dose of pharmacologic agent, introducing the doseof pharmacologic agent into the light transmissive liquid, inserting thecatheter into the lumen, directing the catheter to the site, flowing thelight transmissive liquid, containing the pharmacologic agent, throughthe conduit for discharge at the distal end into the lumen adjacent thesite contemporaneously with light or laser energy delivery via the lighttransmissive liquid. The term "contemporaneously" means during orproximately before or after, as applicable to the treatment.

Using a liquid core laser catheter for treatment of thrombosis orathlerosclerosis can thereby be augmented by the additionaladministration of high-dose pharmacologic therapies at the sitecontemporaneous with the discharge of light energy from the catheter tohelp remove residual thrombus or prevent recurrence of thrombosis orathlerosclerosis.

The foregoing and other objects, features and advantages of theinvention will become more readily apparent from the following detaileddescription of a preferred embodiment of the invention which proceedswith reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a liquid core laser drug deliverysystem according to the present invention.

FIG. 2 is a cross-sectional view taken along lines 2--2 of FIG. 1.

FIG. 3 is a lengthwise sectional view of the distal end portion of thesystem of FIG. 1 shown in an arterial lumen in proximity to a bloodclot.

DETAILED DESCRIPTION

In the following description of a preferred embodiment of the invention,I now describe a system for locally delivering a pharmacologic agent oractive agent in conjunction with delivering laser energy to a site in abody lumen. Those skilled in the art will appreciate that the inventionhas particular utility in treating obstructions in the cardiovascularsystem such as atheromatous plaque, an atheroembolus, thrombus, andblood clots. In addition, in its broader aspects, the invention hasutility in medically treating tumors, lesions, kidney stones, gallstones, polyps, and the like.

FIG. 1 illustrates the liquid core laser drug delivery system 10 of thepresent invention, shown in schematic form. System 10 must be capable ofdelivering an active agent within a body lumen to the site to betreated. In addition, system 10 must be capable of transmitting a pulseof laser energy to the site. The advantages of using a liquid core laserduring angioplasty, for example, is discussed by Gregory et al. in thearticle "Liquid Core Light Guide for Laser Angioplasty", IEEE Journal ofQuantum Electronics, Vol. 26, No. 12, December 1990.

In general terms, system 10 comprises a tube or catheter 12 having aflexible distal end 14 for insertion into a lumen, an external source 16of laser energy coupled to optical fiber 30, an external source 18 oflight transmissive liquid, and an external source 20 of the activeagent. Catheter 12 includes any medical device designed for insertioninto a body lumen to permit injection of fluids, to keep the body lumenopen, or for any other purpose. The present invention has applicabilityfor use within any body lumen including, among others, an artery, avein, a ureter, a common bile duct, a trachea, a bronchus, agastrointestinal tract, a bypass graff, and a graft or prosthesis usinggortex, dacron or other synthetic materials, and a stent composed ofmetal or other materials or combination of materials.

System 10 can also include a guidewire 22 which guides the distal end 14to the site. As shown in FIG. 2, the catheter 12 encloses conduit 24,having sidewall 32, which is filled with a transparent liquid having asuitable index of refraction. The conduit's sidewall defines a lumenalsurface and has either a reflective internal surface (e.g., a metalcoating) or suitably low index of refraction compared to the lighttransmissive liquid to allow internal reflection of light through whichthe liquid flows. Liquid is introduced at the proximal end of theconduit 24 from the liquid source 18. The liquid is discharged into theconduit 24 by way of a liquid injector pump or manual syringe 26. Theliquid is coupled into the conduit 24 using a coupling means 28 such asa Y-adapter.

To practice the invention, I first prepare a dose of the pharmacologicagent which I either add directly to the source 18 or optionally keepthe dose ready in syringe 20 or other means of injecting a prescribedvolume or amount of the agent into the optical stream. Virtually anyconcentration of pharmacologic agent in solution can be used dependingupon the desired medical effect. For example, in the treatment ofintravascular thrombosis urokinase 250-1,000,000 units, streptokinase250-1,000,000 units, recombinant tissue plasminogen activator 25-150 mg,heparin 2500-10,000 units, hirudin, argotropin, hirulog or otheranticoagulants, gene products, enzymes, antiplatelet agents,anti-proliferative agents or combinations thereof can be added to theoptical fluid. Other agents that are also deployed to combat thrombosisor its sequelae could also be added to the fluid as long as solution ofsuch agents did not decrease the ability to transmit light through thefluid. The treatment of thrombosis is only one of the many medical usesfor this invention.

Next, as illustrated in FIG. 3, I insert catheter 12 into lumen 62 andguide the catheter to the site 64 that I have selected for treatment. Byway of example only, the present invention can be used for localdelivery of a pharmacologic agent to an atheromatous plaque, anatheroembolus, a thrombus, a blood clot, a lesion, a kidney stone, agall stone, a tumor, or a polyp.

Preferably, I use a guidewire 22 to position the distal end 14 ofcatheter 12 adjacent the selected site 64. Once I have positioned thedistal end 14 adjacent the site 64, 1 introduce light transmissiveliquid 60, containing the dose, at the proximal end of the conduit 24from the liquid source 18. Liquid discharge means 26 discharges theliquid 60 into the conduit 24. I then direct and couple laser energyfrom a source of laser energy 16 into the proximal end of optical fiber30. Fiber 30 launches the laser energy into the liquid 60. The energypasses within the liquid filled conduit 24 toward distal end 14. Theproportion of the energy introduced into the liquid 60 that emerges fromthe distal end 14 of the liquid filled conduit 24 depends upon thedimensions and physical characteristics of the liquid and upon theconduit sidewall 32, and on the extend to which the catheter 12 followsa curving course. Optionally, either before or after I activate thelaser energy source, I introduce the active agent in solution from thesource of active agent 18 into the stream of flowing liquid 60 bydepressing syringe 20.

I select materials for sidewall 32 and for liquid 60 based in part toprovide a high degree of internal reflection at the conduit surface.Specifically, sidewall 32 and liquid 60 are each transparent to laserenergy which is conducted through the conduit 24 while the index ofrefraction N_(w) of side wall 32 is less than the index of refraction ofN_(f) of liquid 60. Further, I select material for sidewall 32 in partto provide structural strength as well as flexibility so that theliquid-filled conduit 24 can be bent through curves of small radiuswithout kinking or substantially distorting the cross sectional geometryof the conduit 24. I prefer to make sidewall 32 out of a fluorinatedethylenepropylene which is available commercially, for example, FEPTeflon® a DuPont product, THV-tetrafloroethylene hexafloropropylene andvanillidine floride, a 3M product, or a coating of suitably lowindex-of-refraction optical media. If an internal metallized reflectivesurface coating is used, the sidewall need not be optically transparent.

The light transmissive liquid 60 is injectable, transparent in laserwavelengths, and has a refractive index greater than the refractiveindex of sidewall 32. Suitable liquids include solutions of sugars suchas mannitol, glucose, dextrose, and iodinated contrast media. I prefer asolution having a refractive index of about 1.4. For example, FEPTeflon® has a refractive index of about 1.33, thus, the ratio ofrefractive indices relative to such solutions is approximately 1.1. Aratio of 1.1 provides for substantially total internal reflection evenat fairly steep angles of incidence. I prefer that the surface ofsidewall 32 be smooth because if it is not, surface roughness canproduce unsatisfactory irregularities in angle of incidence.

The liquid-filled conduit 24 generally has an inside diameter of about100 to 3000 micrometers. The thickness of the sidewall 121 is generallyless than 0.010 inches. A conduit that is 110 cm long, has an interiorsidewall of FEP Teflon® and contains a sugar solution or contrastmedium, can transmit about 40-60% of the laser energy at 480 nm to thedistal end to be launched through a refractive index-matched lens orwindow into the proximal end from a laser. I prefer to launch laserenergy from the optical fiber 30 into the fluid stream at a distancefrom the tip of catheter 112 to a position ranging about 20 cm withdrawnfrom the distal end 14. The shorter the distance from the launch pointto the distal aspect of the catheter, the higher the percentagetransmission of laser energy.

The diameter of catheter 12 is about 0.1-3 mm depending upon thediameter of the body lumen. Some materials that are optically suitablefor use as a catheter sidewall are structurally unsuitable or lesssuitable because they are insufficiently flexible, or they collapse orkink or otherwise are distorted when they are bent through curves ofsmall radius.

The liquid core laser drug delivery system 10 operates generally asfollows, with specific reference to its use for ablating andpharmacologically treating arteries or veins occluded by thrombus. Fillconduit 24 with liquid, and then couple a source 18 of liquid to theproximal end of conduit 24. Introduce the liquid-filled conduit 24,distal end first through an opening in the skin and through the wall ofa large artery such as the femoral artery. Then direct the cathetertoward the selected site, until the distal end 14 is directed toward theocclusion. Then activate the laser energy source 16 to produce laserenergy having the desired wavelength and pulse duration and intervals.

Optionally, system 10 can include a laser optical scope, as shown inFIG. 1. The laser optical scope must be capable of performing threefunctions within the lumen. The first two of these relate to theillumination and imaging of the interior of the lumen to enable thescope's operator to successfully propagate the distal end of the systemthrough the lumen to the site. Accordingly, the output from a source ofvisible light, such as a Halogen or Xenon lamp 40, is directed to theproximal ends of optical fibers 42 and 44. The other (distal) end ofthese fibers is housed within the flexible catheter 12 and enable it tobe fed through the lumen. A coherent bundle of optical fibers 46 locatedadjacent to optical fibers 42 and 44 within the catheter 12 receives theimage from the illuminated interior of the lumen and transmits itthrough an excluding means 48 to a viewing port 50 where the image canbe monitored by the operator as the flexible catheter 12 is beingpositioned inside the lumen. Alternatively, the image can be transmittedto a video camera 52 which displays the image on the video monitor 54for viewing by the operator. A filter must be placed prior to theeyepiece or imaging equipment to filter out the majority of the laserlight to prevent injury to the viewer's eye or saturation or damage to aCCD imager.

Embodiments of the invention which include an optical scope allow theoperator to monitor the progress of catheter 12 through the lumen viaviewing port 50 without interruption or alternatively in monitor 54.Once the distal end has reached the site and is directed toward thetarget, a further quantity of liquid can be introduced into the catheterfrom the liquid source 18, causing some liquid to emerge from the distalend of the catheter toward the site. Blood situated between the catheterand the site can interfere with laser ablation of the plaque, becausethe blood absorbs nearly all wavelengths of laser energy. The liquidpassing from the distal end 14 of the catheter 12 displaces bloodbetween the catheter and the site removing this interference. As theemerging liquid displaces the blood, it provides a liquid channel distalto the distal end of the catheter for passage of laser energy to thesite, as best seen in FIG. 3. Moreover, the index of refraction of bloodis about 1.34, sufficiently low relative to that of the liquid that theblood surrounding the liquid in this channel can form an effective lightguide between the distal end of the catheter and the site. In such atemporary liquid-core, the liquid-clad light channel can be effectiveover distances in the order of about a centimeter for time intervalsgenerally sufficient in usual circumstances to complete the ablation andopen the arterial lumen.

Then the laser energy source 16 is activated to produce laser energyhaving the desired wavelength and pulse duration and intervals. Theprogress of the laser ablation of the site can be observed through theviewing port 50 or video monitor 54, as the liquid serves not only as alight guide component but also to flush the blood away from the target.When the ablation and drug delivery are completed, I withdraw theliquid-filled catheter from the lumen.

Optionally, I use a guidewire 22 in the above-described procedure, forexample, if the walls of the arteries to be traversed by the catheterthemselves contain plaque formations that would interfere with thepassage of the distal end of the tube during insertion.

Having described and illustrated the principles of the invention in apreferred embodiment thereof, it should be apparent that the inventioncain be modified in arrangement and detail without departing from suchprinciples. I claim all modifications and variations coming within thespirit and scope of the following claims.

I claim:
 1. A method for contemporaneously applying light energy andlocally delivering pharmacologic therapy to a selected site in a bodylumen using a liquid core laser catheter, the catheter including aflexible tube having a distal end for insertion into the lumen, aconduit housed within the tube, means for coupling a flow of lighttransmissive liquid from an external source into the conduit, means fortransmitting light energy from a light energy source into the conduit,the conduit having a sidewall capable of reflecting light into theliquid in the conduit so that the liquid guides the light energy throughthe conduit to the site, the method comprising the steps of:preparing adose of pharmacologic agent; introducing the dose of pharmacologic agentinto the light transmissive liquid; inserting the catheter into thelumen; directing the catheter to the site; flowing the lighttransmissive liquid, containing the pharmacologic agent, through theconduit for discharge at the distal end into the lumen adjacent thesite; and delivering light energy through said conduit via the lighttransmissive liquid to the distal end of the conduit to irradiate thesite contemporaneously with discharge of the pharmacologic agent.
 2. Themethod of claim 1 wherein the pharmacologic agent is selected from oneor more of the group consisting of urokinase, streptokinase, recombinanttissue plasminogen activator, heparin, hirudin, argotropin, hirulog,anticoagulants, enzymes, anti-platelet agents, anti-proliferativeagents, and gene products.
 3. The method of claim 1 wherein the lighttransmissive liquid is injectable and transparent in laser wavelengths.4. The method of claim 1 wherein the light transmissive liquid comprisesa liquid selected from the group consisting of mannitol, glucose,dextrose, and iodinated contrast medium.
 5. The method of claim 1wherein the light energy is laser energy.
 6. The method of claim 1wherein the light energy is incoherent light.
 7. The method of claim 1including selecting materials for use as the conduit and the lighttransmissive liquid which have relative indices of refraction such thatthe conduit sidewall is an optically transparent material having anindex of refraction less than an index of refraction of the lighttransmissive liquid so as to be capable of reflecting light into theliquid in the conduit.
 8. The method of claim 1 including forming theconduit sidewall with a metallic reflective internal coating forreflecting light into the liquid in the conduit.
 9. The method of claim8 wherein the light transmissive liquid comprises saline solution. 10.The method of claim 1 wherein the lumen is selected from the groupconsisting of an artery, a vein, a ureter, a common bile duct, atrachea, a bronchus, a gastrointestinal tract, a bypass graft, a stent,and a prothesis or graff composed of synthetic materials.
 11. The methodof claim 1 wherein the site is selected from the group consisting of anatheromatous plaque, an atheroembolus, a thrombus, a blood clot, alesion, a kidney stone, a gall stone, a tumor, and a polyp.
 12. A methodfor contemporaneously applying laser energy and locally delivering aflow of pharmacologic agent to a selected site in a body lumen using aliquid core laser angioscope catheter, the catheter including a flexibletube having a distal end for insertion into the lumen, a conduit housedwithin the tube, means for coupling a flow of light transmissive liquidfrom an external source into the conduit, means for transmitting visiblelight from an external source through the tube to illuminate the site,means disposed in the distal end of the tube for imaging the illuminatedsite and transmitting a visible image thereof through the tube to anexternal viewing port, means for transmitting laser energy from anenergy source into the conduit, the conduit having a sidewall capable ofinternally reflecting light into the liquid in the conduit so that theliquid waveguides the laser energy through the conduit to the site, themethod comprising the steps of:preparing a solution of the pharmacologicagent; inserting the catheter into the lumen; directing the catheter tothe site; transmitting visible light to the site; flowing the lighttransmissive liquid through the conduit; viewing the site through thelight transmissive liquid; transmitting laser energy through the lighttransmissive liquid flowing through the conduit to treat the site; andintroducing a flow of the pharmacologic agent in solution into theconduit for discharge at the distal end into the lumen adjacent the sitecontemporaneously with the transmission of laser energy to the site.